CN100336792C - Total synthesis method for preparing receme alkannin - Google Patents
Total synthesis method for preparing receme alkannin Download PDFInfo
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- CN100336792C CN100336792C CNB2005100252431A CN200510025243A CN100336792C CN 100336792 C CN100336792 C CN 100336792C CN B2005100252431 A CNB2005100252431 A CN B2005100252431A CN 200510025243 A CN200510025243 A CN 200510025243A CN 100336792 C CN100336792 C CN 100336792C
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Abstract
The present invention relates to a total synthesis method for preparing racemate alkannin, which belongs to the technical field medicine. In the present invention, naphthaldehyde protected by a protecting group is used as a raw material; the naphthaldehyde is heated to react with a 1-halogeno-3-methyl-2-butene metal compound in aprotic polar solvent; an alpha-addition reaction is carried out by regioselectivity; a side chain of shikonin is introduced, so 2-(1-hydroxy-4-methyl-3-pentenyl)-1, 4, 5, 8-tetramethoxy naphthalene or 2-(1-hydroxy-4-methyl-3-pentenyl)-1, 8: 4, 5-double (methylenedioxy) naphthalene is obtained. The protecting group is removed by oxidation to obtain racemized shikonin. The present invention has the advantages of few synthesis step and high reaction yield; besides, the raw materials are easy to obtain, and the present invention is suitable for industrial production.
Description
Technical field
That the present invention relates to is a kind of preparation method who belongs to medical technical field, specifically, is a kind of complete synthesis method for preparing the raceme Shikonin.
Background technology
Shikonin (shikonin) is the effective constituent in the Chinese medicine Asian puccoon, has the various biological activity, as antibiotic, anti-inflammatory, antiviral, antitumor, antifertility, hyperfunction, the anti-immunocompromised of antithyroid, hypoglycemic, liver protecting etc.With the Shikonin be main component be used for the treatment of burn medicine Asian puccoon finish and ointment is used for clinical in China, Japan, Europe; Also entered clinical study as antitumour drug, Shikonin is a very strong topoisomerase enzyme inhibitor; In recent years, the research of the anti-HIV infection of Shikonin is noticeable.With the Shikonin is that lead compound exploitation anti-inflammatory, research antitumor, new antiviral drug have become the hot subject in this field.In addition, Shikonin still is good natural pigment, has been widely used in food, makeup and the printing and dyeing industry, and demand is huge.Though the Asian puccoon wild resource is than horn of plenty, along with a large amount of collections of people, at present near exhausted.Though China has carried out a large amount of artificial cultures, also be difficult to satisfy growing needs.The Japan scholar has carried out the Study on tissue culture of a large amount of Shikonins, and has entered suitability for industrialized production, but cost is still very high.The natural resource of Asian puccoon distribute extremely limited, can't adapt to production in enormous quantities.Therefore, preparing Shikonin with chemical synthesis, is an approach easily and effectively.
Find by prior art documents, Japan scholar (Terada, A.etl, Synthesis ofShikalkin (Shikonin) and Related Compounds.Bull.Chem.Soc.Jpn.1987,60,205.) (raceme Shikonin and related compound thereof synthetic, Japanization association will) reported first Shikonin complete synthesis.The bromo 2-butanone that they protect with the naphthaldehyde and the ethylene glycol of tetramethoxy protection carries out grignard reaction and forms four carbon unit compounds; introduce a methyl with the iodate methyl magnesium again; formation contains six carbon side chain compounds, uses CAN (ceric ammonium nitrate) to become the naphthazarin derivative with silver suboxide through two-step oxidation again.The secondary carbon hydroxyl of naphthazarin derivative on highly selective acylation protection parent nucleus and side chain got the triacetyl compound, use SOCl then
2Eliminate terminal hydroxyl Cheng Shuanjian, finish the structure of Shikonin side chain.Last hydrolysis goes protecting group to generate the raceme Shikonin.The synthetic grignard reaction that carries out twice of this method divides secondary demethylation protecting group, and synthesis step is many, and synthetic total recovery is 1.8% (in naphthaldehyde).
(K.C.Nicolaou and David Hepworth.Concise and Efficient TotalSynthesis of Alkannin and Shikonin.Chem.Int.Ed.1998 such as Nicolaou; 37; 8390 (succinct effective complete synthesis Shikonin and A Kaning; the international version of Germany's applied chemistry) from 1; 8:4; two (the methylene radical dioxy base) naphthalenes of 5-set out; behind bromo; directly introduce hexa-atomic carbon side chain with Weinreb aminocompound reaction and get carbonyl derivative, after asymmetric reduction, go protecting group to obtain Shikonin.This reactions steps is few, and yield is higher.Its weak point is: this reaction adopts positive fourth lithium in low temperature-78 ℃ reaction down, the Weinreb aminocompound N-methoxyl group-N-methyl-4-methyl-3-hexene acid amides that uses is not easy to obtain, and asymmetric reduction reagent two different firpene base borine muriate DIP-Cl cost an arm and a leg.
Have the total synthesis method (Vassilios that a plurality of study group have reported Shikonin respectively in the past in the more than two decades, The Chemistry and Biology of Alkannin, Shikonin, and relatedNaphthazarin Natural Products, Angew.Chem.Int.Ed.1999,38.270) (A Kaning, the chemistry and biology of Shikonin and relevant naphthoquinones class natural product, the international version of German applied chemistry).These synthetic methods or synthetic route are long, reaction yield is low or raw material is not easy to obtain, severe reaction conditions, are not suitable for suitability for industrialized production.
According to the retrosynthetic analysis of Asian puccoon Asian puccoon,, can introduce the six carbon side chains (seeing reaction formula 1) of Shikonin through single step reaction with the naphthaldehyde of protection and the organometallics addition of isopentene.
Reaction formula 1
Have the scholar to attempt with the synthetic Shikonin of this method, but do not succeed, reason is under usual conditions, the main γ-affixture (1) that generates of aldehydes or ketones and the reaction of isopentene group metallic compound.And be difficult to obtain needed α-affixture (2) (seeing reaction formula 2)
Reaction formula 2
Japanese Patent (clear 63-112531) discloses a similarly reaction, with 1,4,5, the Grignard reagent reaction of 8-tetramethoxy naphthalene-2-formaldehyde and 4-chloro-2-methyl-1-butene alkene, generate 2-(1-hydroxy-4-methyl-4-pentenyl)-1,4,5,8-tetramethoxy naphthalene, the isomerization problem that this reaction has avoided using the metallic compound of isopentene to produce with the carbonyl compound addition, but the addition products therefrom is not the synthetic required side chain of Shikonin, and need change into Shikonin through polystep reactions such as cyclization, demethylation, open loop, dehydrations again.
Summary of the invention
The objective of the invention is to overcome the deficiencies in the prior art, provide a kind of raceme Shikonin complete synthesis preparation method, make that its raw material is easy to get, synthesis step is few, the reaction yield height is fit to suitability for industrialized production.
The present invention is achieved by the following technical solutions, concrete steps of the present invention following (seeing reaction formula 3):
Reaction formula 3
1.. the naphthaldehyde (3) with the protecting group protection is a raw material, and with organometallics (4) reaction of 1-halo-3-methyl-2-butene, single stage method is introduced the isopentene group side chain, finishes the structure of Shikonin side chain.
2. use isopentene zinc bromide reagent and 1,4,5,8-tetramethoxy naphthalene-2-formaldehyde or 1,8:4, two (methylene-dioxy) naphthalenes of 5--2-formaldehyde reacting by heating in non-proton polarity solvent obtain α-adduct 2-(1-hydroxy-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxy naphthalene (5) or 2-(1-hydroxy-4-methyl-3-pentenyl)-1,8:4, two (methylene-dioxy) naphthalenes (6) of 5-.
3.. the above-mentioned 2-that obtains (1-hydroxy-4-methyl-3-pentenyl)-1,4,5; 8-tetramethoxy naphthalene or 2-(1-hydroxy-4-methyl-3-pentenyl)-1,8:4, two (the methylene radical dioxy base) naphthalenes of 5-; slough protecting group through oxidation again, obtain racemic Shikonin (7).
Described 2-(1-hydroxy-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxy naphthalene or 2-(1-hydroxy-4-methyl-3-pentenyl)-1,8:4, two (methylene-dioxy) naphthalenes of 5-synthetic:
With the naphthaldehyde of protecting group protection and metallic compound reacting by heating in non-proton polarity solvent of 1-halo-3-methyl-2-butene, carry out to regioselectivity α-addition reaction.Organometallics is muriate, bromide or the iodide of metallic zinc, copper; The bromo-derivative of preferable alloy zinc.Non-proton polarity solvent is hexamethyl three phosphamides, N-Methyl pyrrolidone, 1, the 3-dimethyl-imidazolinone; Temperature of reaction is between 100-150 ℃.
Specifically: under the normal temperature nitrogen protection; drop into the naphthaldehyde (0.01mol) and the non-proton polarity solvent (0.05-0.50mol) of protecting group protection; drip (0.05-0.50mol) isopentene organometallics that has prepared; react after 1-4 hour; steam tetrahydrofuran (THF); under 100-150 ℃; reacted 10-72 hour; the reaction postcooling; with (10-200ml) saturated aqueous ammonium chloride solution hydrolysis, with ethyl acetate (30-300ml/3) extraction; the salt washing; anhydrous magnesium sulfate drying steams solvent; get α-adduct 2-(1-hydroxy-4-methyl-3-pentenyl)-1; 4,5,8-tetramethoxy naphthalene or 2-(1-hydroxy-4-methyl-3-pentenyl)-1; 8:4, two (methylene-dioxy) naphthalenes of 5-.
Described 5,8-dihydroxyl-(1-hydroxy-4-methyl-3-pentenyl)-1, the preparation of 4-naphthoquinones (Shikonin):
With α-adduct 2-(1-hydroxy-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxy naphthalene or 2-(1-hydroxy-4-methyl-3-pentenyl)-1,8:4, two (methylene-dioxy) naphthalenes (0.01mol) of 5-dissolve in acetonitrile-aqueous solution or the acetone-water solution (20-200 times of volume) of 10-90%, adding one has in the electrolyzer of two platinum electrodes, with the lithium perchlorate of 0.1-2M or TBAP solution as electrolytic solution, at normal temperatures, under the voltage of 1-3V, carried out stopped reaction electrolysis 10-72 hour, with the organic solvent evaporate to dryness in the reaction solution, use chloroform extraction, anhydrous sodium sulfate drying is used in the salt washing, and the gained crude product gets 5 with re-crystallizing in ethyl acetate, 8-dihydroxyl-(1-hydroxy-4-methyl-3-pentenyl)-1,4-naphthoquinones (Shikonin).
The invention has the beneficial effects as follows: the naphthaldehyde with the protecting group protection is a raw material; organometallics reaction with 1-halo-3-methyl-2-butene; single stage method is introduced the isopentene group side chain; compare with the synthetic method of bibliographical information; raw material is easy to get, synthesis step is few; reaction yield height, synthetic total recovery reach 52%-73% (naphthaldehyde in the protecting group protection is a benchmark), are suitable for mass preparation.Use N-Methyl pyrrolidone, 1 in addition, the 3-dimethyl-imidazolinone substitutes deleterious hexamethyl three phosphamides as non-protonic solvent, helps health environment-friendly.
Embodiment
Embodiment 1:2-(1-hydroxy-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxy naphthalene
Under the normal temperature nitrogen protection, drop into 1,4,5,8-tetramethoxy naphthalene-2-formaldehyde (0.01mol) and hexamethyl three phosphamides (0.50mol) drip the isopentene zinc bromide reagent (0.50mol) that has prepared.React after 1 hour, steam tetrahydrofuran (THF), reacted 72 hours down at 130 ℃, the reaction postcooling is with the saturated aqueous ammonium chloride solution hydrolysis of 200ml, with ethyl acetate 300ml/3 extraction, salt solution washing, anhydrous magnesium sulfate drying, steam solvent, get crude product,, get 2-(1-hydroxy-4-methyl-3-pentenyl)-1 through column chromatography, 4,5,8-tetramethoxy naphthalene, yield 86.4%.
1HNMR(CDCl
3)δ=7.02(s,1H,ArH),6.82(d,1H,ArH),6.80(d,1H,ArH)5.22-5.26(m,2H,CHOH?and?C=CH),3.94(s,3H,OCH
3),3.93(s,3H,OCH
3),3.89(s,3H,OCH
3),3.75(s,3H,OCH
3),2.51-2.54(m,2H,CH
2),1.72(s,3H,CH
3),1.64(s,3H,CH
3)。
Embodiment 2:2-(1-hydroxy-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxy naphthalene
Under the normal temperature nitrogen protection, drop into 1,4,5,8-tetramethoxy naphthalene-2-formaldehyde (0.01mol) and N-Methyl pyrrolidone (0.15mol) drip the isopentene zinc bromide reagent (0.15mol) that has prepared.React after 2 hours, steam tetrahydrofuran (THF), reacted 24 hours down at 150 ℃, the reaction postcooling is with the saturated aqueous ammonium chloride solution hydrolysis of 20ml, with ethyl acetate 30ml/3 extraction, salt washing, anhydrous magnesium sulfate drying, steam solvent, get crude product,, get 2-(1-hydroxy-4-methyl-3-pentenyl)-1 through column chromatography, 4,5,8-tetramethoxy naphthalene, yield 81.9%.
1The H-NMR data are consistent with embodiment 1.
Embodiment 3:2-(1-hydroxy-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxy naphthalene
Under the normal temperature nitrogen protection, drop into 1,4,5,8-tetramethoxy naphthalene-2-formaldehyde (0.01mol) and 1,3-dimethyl-imidazolinone (0.05mol) drips the isopentene zinc bromide reagent (0.05mol) that has prepared.React after 4 hours, steam tetrahydrofuran (THF), reacted 10 hours down at 100 ℃, the reaction postcooling is with the saturated aqueous ammonium chloride solution hydrolysis of 50ml, with ethyl acetate 100ml/3 extraction, salt solution washing, anhydrous magnesium sulfate drying, steam solvent, get crude product,, get 2-(1-hydroxy-4-methyl-3-pentenyl)-1 through column chromatography, 4,5,8-tetramethoxy naphthalene, yield 83.0%.
1The H-NMR data are consistent with embodiment 1.
Embodiment 4:2-(1-hydroxy-4-methyl-3-pentenyl)-1,8:4, two (methylene-dioxy) naphthalenes of 5-
Under the normal temperature nitrogen protection, drop into 1,8:4, two (methylene radical dioxy base)-2-formaldehyde (0.01mol) of 5-and hexamethyl three phosphamides (0.50mol) drip the isopentene zinc bromide reagent (0.15mol) that has prepared.React after 4 hours, steam tetrahydrofuran (THF), reacted 72 hours down at 130 ℃, the reaction postcooling is with the saturated aqueous ammonium chloride solution hydrolysis of 200ml, with ethyl acetate 300ml/3 extraction, salt washing, anhydrous magnesium sulfate drying, steam solvent, get crude product,, get 1 through column chromatography, 2-adduct 2-(1-hydroxy-4-methyl-3-pentenyl)-1,8:4, two (methylene-dioxy) naphthalenes of 5-, yield 85.7%.
1HNMR(CDCl
3)δ=7.03(s,1H,ArH),6.82(d,1HArH),6.80(d,1H,ArH),5.51(d,1H,OCH
2O),5.50(d,1H,OCH
2O),5.46(d,1H,OCH
2O),5.45(d,1H,OCH
2O),5.19(t,1H,C=CH),5.13(dd,1H,CHOH),2.542-2.53(m,2H,CH
2),1.71(s,3H,CH
3),1.61(s,3H,CH
3)。
Embodiment 5:2-(1-hydroxy-4-methyl-3-pentenyl)-1,8:4, two (methylene-dioxy) naphthalenes of 5-
Under the normal temperature nitrogen protection, drop into 1,8:4, two (methylene-dioxy) naphthalenes of 5--2-formaldehyde (0.01mol) and N-Methyl pyrrolidone (0.10mol) drips the isopentene zinc bromide reagent (0.10mol) that has prepared.React after 1 hour, steam tetrahydrofuran (THF), reacted 24 hours down at 150 ℃, the reaction postcooling is with the saturated aqueous ammonium chloride solution hydrolysis of 20ml, with ethyl acetate 30ml/3 extraction, salt washing, anhydrous magnesium sulfate drying, steam solvent, get crude product,, get 1 through column chromatography, 2-adduct 2-(1-hydroxy-4-methyl-3-pentenyl)-1,8:4, two (methylene-dioxy) naphthalenes of 5-, yield 83.2%.
1The H-NMR data are consistent with embodiment 4
Embodiment 6:2-(1-hydroxy-4-methyl-3-pentenyl)-1,8:4, two (methylene-dioxy) naphthalenes of 5-
Under the normal temperature nitrogen protection, drop into 1,8:4, two (methylene-dioxy) naphthalenes of 5--2-formaldehyde (0.01mol) and 1,3-dimethyl-imidazolinone (0.05mol) drips the isopentene zinc bromide reagent (0.50mol) that has prepared.React after 2 hours, steam tetrahydrofuran (THF), reacted 72 hours down at 100 ℃, the reaction postcooling is with the saturated aqueous ammonium chloride solution hydrolysis of 100ml, with ethyl acetate 150ml/3 extraction, salt washing, anhydrous magnesium sulfate drying, steam solvent, get crude product,, get 1 through column chromatography, 2-adduct 2-(1-hydroxy-4-methyl-3-pentenyl)-1,8:4, two (methylene-dioxy) naphthalenes of 5-, yield 70.1%.
1The H-NMR data are with consistent with embodiment 4.
Embodiment 7:5,8-dihydroxyl-(1-hydroxy-4-methyl-3-pentenyl)-1, the preparation of 4-naphthoquinones (Shikonin)
With 2-(1-hydroxy-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxy naphthalene (0.01mol) dissolves in the acetonitrile solution of 100ml50%, add one and have in the electrolyzer of two platinum electrodes, with the lithium perchlorate solution of 1M as electrolytic solution.Under the normal temperature, electrolysis 24h under 1V voltage, after reaction stops, with the organic solvent evaporate to dryness in the reaction solution,, use anhydrous sodium sulfate drying with chloroform extraction, salt washing, the gained crude product gets red needle-like crystal 5 with re-crystallizing in ethyl acetate, 8-dihydroxyl-(1-hydroxy-4-methyl-3-pentenyl)-1,4-naphthoquinones (Shikonin) (1), yield are 79.5%.mp:146~148℃。
1H-NMR(CDCl
3)δ=12.60(s,1H,ArOH),12.50(s,1H,ArOH),7.20(d,2H,2ArH),7.17(s,1H,QuinH),5.20dd,1H,C=CH),4.92(dd,1H,CHOH),2.66-2.62(m,1H,CH
2a),2.38-2.31(m,1H,CH
2b),1.76(s,3H,CH
3),1.66(s,3H,CH
3)。
Embodiment 8:5,8-dihydroxyl-(1-hydroxy-4-methyl-3-pentenyl)-1, the preparation of 4-naphthoquinones (Shikonin)
With 2-(1-hydroxy-4-methyl-3-pentenyl)-1,8:4, two (methylene-dioxy) naphthalenes (0.01mol) of 5-dissolve in the acetonitrile solution of 20ml 90%, adding one has in the electrolyzer of two platinum electrodes, with the TBAP of 0.1M as electrolytic solution, under the normal temperature, under the voltage of 3V, carry out electrolysis 72 hours, stopped reaction, with the organic solvent evaporate to dryness in the reaction solution, use chloroform extraction, anhydrous sodium sulfate drying is used in the salt washing, and the gained crude product gets red needle-like crystal with re-crystallizing in ethyl acetate, 5,8-dihydroxyl-(1-hydroxy-4-methyl-3-pentenyl)-1,4-naphthoquinones (Shikonin), yield are 83.6%.Mp and
1The H-NMR data are consistent with embodiment 7.
Embodiment 9:5,8-dihydroxyl-(1-hydroxy-4-methyl-3-pentenyl)-1, the preparation of 4-naphthoquinones (Shikonin)
With 2-(1-hydroxy-4-methyl-3-pentenyl)-1,8:4, two (methylene-dioxy) naphthalenes (0.01mol) of 5-dissolve in acetone-aqueous solution of 200ml 50%, adding one has in the electrolyzer of two platinum electrodes, with the lithium perchlorate solution of 2.0M as electrolytic solution, under the normal temperature, under the voltage of 3V, carry out electrolysis 10 hours, stopped reaction, with the organic solvent evaporate to dryness in the reaction solution, use chloroform extraction, anhydrous sodium sulfate drying is used in the salt washing, and the gained crude product gets red needle-like crystal with re-crystallizing in ethyl acetate, 5,8-dihydroxyl-(1-hydroxy-4-methyl-3-pentenyl)-l, 4-naphthoquinones (Shikonin), yield are 68.9%.Mp and
1The H-NMR data are consistent with embodiment 7.
Claims (2)
1, a kind of complete synthesis preparation method of raceme Shikonin is characterized in that:
Naphthaldehyde with the protecting group protection is a raw material, with the organometallics reaction of 1-halo-3-methyl-2-butene, Synthetic 2-(1-hydroxy-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxy naphthalene or 2-(1-hydroxy-4-methyl-3-pentenyl)-1,8:4, two (methylene-dioxy) naphthalenes of 5-; Single stage method is introduced the isopentene group side chain, finishes the structure of Shikonin side chain, sloughs protecting group through electrooxidation again, obtains racemic Shikonin.
2, the total synthesis method of raceme Shikonin according to claim 1, it is characterized in that, described 2-(1-hydroxy-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxy naphthalene or 2-(1-hydroxy-4-methyl-3-pentenyl)-1,8:4, synthesizing of two (methylene-dioxy) naphthalenes of 5-, be meant: with the naphthaldehyde of protecting group protection and metallic compound reacting by heating in non-proton polarity solvent of 1-halo-3-methyl-2-butene, carry out to regioselectivity α-addition reaction, introduce the side chain of Shikonin, organometallics is a metallic zinc, copper, the muriate of magnesium, bromide or iodide; Non-proton polarity solvent is hexamethyl three phosphamides, N-Methyl pyrrolidone, 1, the 3-dimethyl-imidazolinone; Temperature of reaction is between 100-150 ℃.
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CN101367717B (en) * | 2008-10-10 | 2011-11-09 | 长沙艾茵生物制品有限公司 | Total synthesis method of despinner alkannin |
CN101863786B (en) * | 2010-06-26 | 2013-05-01 | 上海交通大学 | Water-soluble shikonin naphthazarin oxygen nucleus alkyl derivative and preparation and application methods thereof |
CN102199080B (en) * | 2011-04-08 | 2013-07-03 | 上海交通大学 | Method for preparing shikonin with high optical purity by asymmetric total synthetic method |
CN102617342B (en) * | 2012-03-13 | 2014-04-30 | 上海交通大学 | (+/-)-alkannin naphthazarin parent nucleus oxygen alkyl acylation derivant and preparation method thereof |
US9630912B2 (en) | 2013-01-16 | 2017-04-25 | Shanghai Jiao Tong University | Shikonin, alkannin; and racemic parent nucleus cabonyl oxime derivatives and applications thereof |
Citations (2)
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JPS63112531A (en) * | 1986-10-29 | 1988-05-17 | Kyushu Kogyo Univ | 2-(1-hydroxy-4-methyl-4-pentenyl)-1,4,5,8-tetramethoxy-n aphthalene and production thereof |
JPH032390A (en) * | 1989-05-26 | 1991-01-08 | Osaka Organic Chem Ind Ltd | Production of 5,8-dimethoxy-1,4-naphthoquinone derivative |
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JPS63112531A (en) * | 1986-10-29 | 1988-05-17 | Kyushu Kogyo Univ | 2-(1-hydroxy-4-methyl-4-pentenyl)-1,4,5,8-tetramethoxy-n aphthalene and production thereof |
JPH032390A (en) * | 1989-05-26 | 1991-01-08 | Osaka Organic Chem Ind Ltd | Production of 5,8-dimethoxy-1,4-naphthoquinone derivative |
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